Asthma is a chronic inflammatory disease of respiratory airways in humans. Clinically, in hypersensitive persons the inflammation causes periodical coughing attacks, troubled breathing, wheezing, tightness in the chest and chest pain. The inflammation makes respiratory airways more susceptible to irritations by allergens, chemical irritants, tobacco smoke, cold air and strain. Exposed to these irritants respiratory airways become edematous, contracted, filled with mucus and hypersensitive.
The pathogenesis of asthma is complex and includes the interaction of inflammatory cells, mediators as well as of the tissue and cells of respiratory airways. In asthmatic process an early phase and a late phase of a response are distinguished. Allergic diseases as well as allergen-induced asthma are characterised by the synthesis of a specific type of IgE antibodies. Immediately after the inhalation of allergens, complexes of allergens and allergen specific IgE's are bound to highly affinity IgE receptor (Fcε receptor type I) present on basophils, mastocytes and eosinophils. By the binding to the receptor the activation of signal transfer cascade occurs, which results in:    1. de novo synthesis of proinflammatory genes (e.g. interleukin-4 and interleukin-5),    2. egocytosis of the content of cytoplasmatic granules—degranulation.
The granules contain inflammatory mediators such as histamine, serotonin, leukotrienes C4, D4 and E4, and proteins such as major basic protein and mieloperoxidase. These inflammatory mediators co-operate in the processes of vasodilation, bronchoconstriction, triggering and control of the inflammatory process and activation of the cells and damage to the inflamed tissue. These processes form the early asthmatic response. The inhibition of degranulation may prevent the symptoms and stop the inflammation progress, which has been proven by the clinical use of degranulation inhibitors (sodium chromoglycate, nedocromyl sodium and ketotifen).
The late asthmatic response includes a permanent obstruction of air passages, a hyperreactivity of the bronchi and a development of inflammation changes including the accumulation of neutrophils, eosinophils, lymphocytes and monocytes/macrophages in the respiratory system. The accumulation of inflammatory cells results from harmonized interaction of lymphokines (TNF-α, IL-4, IL-5), adhesion molecules on the surface of leukocytes (integrins) and endothelial cells (selectins), and chemokines (eotaxin, RANTES). The role and significance of T-lymphocytes in asthma were confirmed by the existence of an increased number of activated CD4+ T-cells in bronchoalveolar lavage and bronchial biopsies of patients suffering from asthma. Two subpopulations of CD4+ cells differ with regard to the profile of cytokines they secrete. Th 1 cells secrete IL-2, IL-3, GM-CSF, INF-γ. An activation of Th 1 cells is important in the defence of the host against intracellular organisms, viruses and neoplasms. Investigations have demonstrated that, in asthma, Th 2 cell response prevails with an increased expression of IL-5 that is important in the formation of eosinophilic infiltration typical of allergic inflammation.
Morphologic changes occurring in asthma include an infiltration of the bronchi by inflammation cells (mastocytes, T-lymphocytes and eosinophils are the key executive cells), a clogging of respiratory airways by a secrete, interstition oedema and increased microcirculation permeability. On the basis of pathophysiological findings it has been established that eosinophilic infiltration is specific and differentiates asthma from other types of inflammation.
In the control of asthma two types of medicaments exists, symptomatic ones and basic ones. The symptomatic medicaments include short-acting bronchodilators such as β2-agonists, anticholinergics, teophilin, which rapidly relax the contracted respiratory airways and alleviate the acute symptoms. The basic medicaments include antiinflammatory drugs and long-acting bronchodilators. Antiinflammatory drugs alleviate and prevent the inflammation reaction and they include inhalation corticosteroids, systemic corticosteroids, inhalations of sodium chromoglycate and nedochromil.
Steroid antiinflammatory compounds are still considered to be the most effective medicaments in the treatment of inflammatory diseases and conditions such as asthma. The good potency and efficacy of said type of medicaments are, however, accompanied by numerous undesired side effects, such as disturbances of carbohydrate metabolism, of calcium resorption, of the secretion of endogenic corticosteroids and of physiological functions of the hypophysis, of the suprarenal gland core and of the thymus. In the literature (WO 94/13690, WO 94/14834, WO 92/13872 and WO 92/13873) so-called “soft” steroids or hydrolysable corticosteroids with local action are described. Their systemic, undesired effect is reduced due to the instability of “soft” steroids in serum, where the active steroid is rapidly hydrolyzed to an inactive form. However, a steroid without negative side effects in long-term use still has to be found.
Some compounds of coumarin class (U.S. Pat. Nos. 4,200,577; 4,263,299; 4,731,375; 5,428,038) show antiallergic action in the prevention and treatment of various allergic diseases such as allergic asthma, allergic dermatitis, allergic rhinitis or enteritis, allergic conjunctivitis or allergic eczema.
There are also known more complex dimer and tetramer derivatives of hydroxycoumarin asymmetrically bound by a central alkyl or aryl linker, which demonstrate anti-HIV action (Zhao, H. et al. J. Med. Chem. 1997, 40, 242-249). Similar anti-HIV action is also shown by several products of condensation of hydroxycoumarins possessing more than one hydroxy group per coumarin unit with aromatic or aliphatic mono- or dialdehydes (U.S. Pat. No. 6,100,409 and WO 03/029237).